Animal treatments

ABSTRACT

Compositions and methods for the treatment and control of various conditions in an animal which comprises administering to said animal an effective amount of a immediate release composition of about 0.5% to 50% wt/wt of active ingredient together with excipients to a total of about 100%, wherein said composition dissolves in a relatively short period of time, e.g., 75 seconds or less, 5 seconds or less, or 3 seconds or less, upon administration to said animal.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/014,290 filed on Jun. 21, 2018, which is a continuation of U.S.application Ser. No. 14/275,019 filed on May 12, 2014; which is now U.S.Pat. No. 10,022,361 issued on Jul. 17, 2018, which is a continuation ofU.S. application Ser. No. 13/343,692 filed on Jan. 4, 2012, which is nowU.S. Pat. No. 8,722,636, issued on May 13, 2014, which claims thebenefit of U.S. Provisional Application No. 61/437,763 filed on Jan. 31,2011. The entire contents of these prior applications are incorporatedherein by reference.

BACKGROUND

Therapeutic agents for animals, for example equines, bovines, canines,felines, ovines, and porcines, suffer from numerous drawbacks for avariety of reasons. For example, injectable formulations, which may bepreferred because they provide rapid onset of activity, are mostpreferably administered in an environment of cleanliness to preventinfections at the injection site. However, with domesticated animalsthis may be difficult to ensure in a typical barn, farm, field orracetrack environment where such injectable formulations may beadministered. A further drawback of an injectable formulation is that atypical injectable therapeutic may suffer from a relatively shortduration of activity. Oral dosing formulations for animals suffer fromdifferent drawbacks, in that the animal can spit the formulation out ofits mouth before it is ingested, resulting in a loss of the full dosage.In a circumstance where the oral formulation is administered byintubation, the dosing may suffer from variability of bioavailabilitydue to the inherent and unique characteristics of each animal'sdigestive system, i.e., the amount of food in the animal's stomach, thelength of time since its last feeding, and the animal's levels ofdigestive enzymes, which may vary due to other environmental conditions,etc. Further limitations of existing formulations include stability ofthe active ingredient in the formulation, and possible inadvertent orincorrect dosing of the human administrator with the drug substance.

Most veterinary therapeutics are off-shoots of drugs developed forhumans rather than being specifically developed for the uniquecharacteristics of a specific animal, for example equines, bovines,canines, felines, ovines, and porcines. Due to the high costs associatedwith developing formulations tailored precisely for animals, andobtaining regulatory approval of such formulations for animals, manyveterinarians have a limited repertoire of drugs to utilize in thetherapy of various animal diseases. Thus, the FDA allows “extra-labeluse” of human drugs. See, “Extra-label Drug Use in Veterinary Medicine”,available fromwww.fda.gov/Anima1Veterinary/NewsEvents/FDAVeterinarianNewsletter/ucm100268.htm. This practice has resulted in formulations of human drugs bycompounding pharmacists at the request of veterinarians, i.e, so-called“custom compounding,” in order to enlarge therapeutic armamentariumavailable to veterinarians. See, for instance, the brochure published bythe FDA entitled “Veterinary Compounding” available fromwww.avma.org/issues/druas/compoundina/veterinary_compoundingbrochure.asp

Therefore, there exists a need to provide improved therapeutic methodsfor animals, for example equines, bovines, ovines, canines, felines andporcines which obviate many of the disadvantages and side effects of thecommonly used injectable and oral formulations.

There further exists a need to provide methods for the treatment ofanimals, for example equines, bovines, canines, felines, ovines, andporcines with drug products which give an earlier onset of action, alongwith a concomitant reduction in side effects including risk of infectionat injection sites or bioavailability issues resultant from theabsorption of the drug from the digestive tract of the animal.

There also exists a need to provide methods which enable treatment ofthe animal patient which reliably and predictably provides forregulatory clearance of the drug. For example, in animals participatingin competition, the drug clears the animal's system so that it mayundergo treatment without drug residues remaining which would disqualifyit from competition. Since the clearance of a drug administered via themethods of the present disclosure is more rapid, the animal may onlyneed to discontinue therapy for a relatively short period of time, thusminimizing the effect of discontinuance for several days, resulting in are-establishment or increased severity of the disease under treatment.

Disclosed herein are animal treatment methods and compositions, forexample for the treatment of animals, for example equines, bovines,canines, felines, ovines, and porcines. Various embodiments compriseadministration of a therapeutic agent into the bloodstream of the animalvia a formulation administered via the oral cavity. In variousembodiments, a majority of the formulation may be absorbed prior toreaching the gastric mucosa. In certain embodiments, the formulation maybe adapted for animals, for example equines, bovines, canines, felines,ovines, and porcines to dissolve in a relatively short period of time,e.g., 75 seconds or less. Such administration of the formulation may, inat least certain embodiments, result in faster onset of the therapy,diminished occurrences of the side-effects due to non-uniformity ofbioavailability of the active agent, and/or more accurate dosing, whichmay, in at least some embodiments, result in dose lowering. Further, inat lease some embodiments, such administration may result in a greaterportion of the therapeutic agent actually being directly introducedsystemically into the circulatory system for its therapeutic effect.

Also disclosed herein are methods for the treatment and control ofvarious diseases afflicting animals, for example equines, bovines,canines, felines, ovines, and porcines, with improved safety for theboth the animal and the person administering the therapeutic agent.

In at least certain exemplary embodiments, the compositions and methodsare useful for administration to humans.

DETAILED DESCRIPTION

Therapeutic agents, such as, for example, clenbuterol, imiprazole,omeprazole, detomidine, acepromazine, flunixin, moxidectin andpraziquantel have been typically administered orally. For example, indomesticated animals these agents may be administered in the form offeed concentrates, feed additives, tablets, oblets, boluses, gels,pastes, or the like, or have been administered parenterally as aninjectable. Of the above-mentioned formulation types, arguably the mostsuitable for ease of administration, efficiency, and effective dosage,as well as economic and practical application of the endoparasiticidalagents moxidectin and praziquantel which are often included, is an oralgel or paste. Feed additives and feed concentrates are unsuitable due tothe lack of stability of many active ingredients in the presence ofmoisture and/or excipients utilized in feeds, and the lack of packagingand storage conditions ensuring accurate dosing to animals of variableweight. Tablets, boluses, oblets, and drenches are often cumbersome toadminister to large numbers of animals effectively, and parenteralinjection is more stressful for the animal and the handler.

Further, oral administration of therapeutic agents suffer thedisadvantages of exposure to the gastric environment which results indegradation metabolism when absorbed through the gastric mucosa andgastric and/or hepatic metabolism, resulting in reduced levels of thetherapeutic agent available for the treatment of the disease.

Surprisingly, it has now been found that therapeutic agents may beformulated in a so-called “fast-acting” or “immediate release”formulation and conveniently administered to the circulatory system ofthe animal via a formulation administered via the oral cavity, themajority of which is absorbed prior to the gastric mucosa. In variousembodiments the thereapeutic agents may be adapted for animals, such as,for example equines, bovines, canines, felines, ovines, and/or porcinesto afford therapeutic effects without the concomitant disadvantages ofthe prior art formulations. In further embodiments, the formulations maybe adapted for humans.

Non-limiting exemplary fast release formulations may include those suchas the multiparticulate fast disintegrating tablets disclosed, forinstance in U.S. Pat. No. 6,596,311; the so-called rapidly dispersing“3-D platform”, disclosed in U.S. Pat. No. 6,471,992; pectin-baseddissolvable films, such as disclosed in US2007/0042023; the teachings ofall of which are incorporated herein by reference. In the veterinarytherapeutic technology space, such fast release formulations wereoriginally developed for human use and were designed to be administeredorally, rather than directly to the circulatory system of the recipientvia a formulation administered via the oral cavity, the majority ofwhich is absorbed prior to the gastric mucosa, thus providing directsystemic introduction (“DSI”).

These fast release formulations may comprise the active therapeuticagent, typically in combination with acceptable excipients such asgelatin, mannitol or another sugar alcohol, together with suitablesweetening agents, such as aspartame, and suitable flavoring agents suchas mint flavoring, for example peppermint, fruit flavors, and/ormeat/fish flavors.

The fast/immediate release formulations described herein aremanufactured using suitable excipients in accordance with the techniquesand processing disclosed in the aforementioned U.S. Pat. No. 6,596,311.In at least certain embodiments, the formulations are rapid releaseformulations, having faster release times that typical formulations fornon-controlled release (e.g., immediate release). In variousembodiments, the active ingredient, either as a free base or awater-soluble salt, may be dissolved or suspended in water or anothersuitable solvent, together with various excipients, and subjected to aprocess such as freeze-drying in order to provide immediate releasecompositions in which the active ingredient is relatively stable, andwhich can provide, upon administration, therapeutically useful levels ofthe active ingredient.

In a typical formulation according to various embodiments of thedisclosure, the active ingredient may comprise from about 0.5 to about50% by weight of the composition, such as, for example, about 1.0 toabout 10% by weight of the composition, or about 5% by weight of thecomposition, depending upon the particular active chosen and the totalamount of the active ingredient which is needed to administer to theanimal under treatment.

In human dosing, traditional immediate release formulations provide forthe nonmodified, as opposed to controlled or sustained, release of theactive ingredient in the stomach. Traditional sublingual doses dissolvequickly under the tongue, but none-the-less can be thought of asimmediate-release formulations. In recent years, “rapid release”technologies have been developed which speed up the release profile overtraditional formulations, particularly in the stomach. The compositionsand methods of administration contemplated herein involve both immediaterelease dosing and rapid release dosing to the circulatory system of theanimal in a formulation administered via the oral cavity, the majorityof which is absorbed prior to the gastric: mucosa, adapted for humans,equines, bovines, canines, felines, ovines, and porcines. Unlessspecifically noted otherwise, “immediate release” shall includetraditional immediate release (i.e., not controlled or sustainedrelease).

We have now found that administering therapeutic agents via the oralcavity, where the majority is absorbed prior to the gastric mucosa,i.e., under the tongue (sublingual), on the top of the tongue, and/orbetween the cheek (buccal), to animals, results in rapid onset ofactivity, more accurate and lowered dosing, an absence or diminishmentof side-effects, and greater safety to both the animal and theadministrator of the formulation.

As used herein, the term “oral cavity” means that portion of thealimentary canal from the orifice conventionally referred to as themouth, including, for example the area distally from the mouth to theesophagus and all tissues including, for example the mucal membranes,epithelium, cheek, tongue (e.g., under, on or around the tongue) andgums.

As used herein, the term “non-gastric mucosa” refers to the pre-gastricmucosal cells, e.g., oral mucosa, including the mucous membrane beneaththe tongue, and/or the buccal mucosa at the inside of the cheek and gumand absorption sites in the esopaghus.

As used herein, the term “pre-gastric” refers to all parts of thealimentary canal beginning at the mouth and continuing to the juncturewith the secretory stomach.

As used herein, “Direct Systemic Introduction” (“DSI”), meansadministering one or more therapeutically active agent(s) directly tothe circulatory system of an animal via a formulation administered andabsorbed in the oral cavity and/or the non-gastric mucosa. DSI may, inat least some embodiments, provide relatively high systemicconcentrations of the active agents, e.g. by allowing agents to passdirectly into the systemic circulation avoiding the destructiveactivities in the digestive tract by gastric breakdown, metabolism inthe wall of the GI tract and first pass metabolism by the liver. DSI mayresult in higher systemic availability of therapeutic agents in theanimal for their desired therapeutic effects, when compared to productsformulated in conventional oral delivery systems.

DSI can provide advantages over traditional oral, intravenous,intramuscular, and subcutaneous routes of administration, in that moreof the drug may be available systemically for its desired therapeuticeffects. For example, in equines, DSI can provide more rapid metabolicclearance of the drug, resulting in a shortened withdrawal time to clearthe animal for performance racing. See, e.g., “Equine Drug Testing andTherapeutic Medication Regulation: 2009 Policy of the NationalHorsemen's Benevolent and Protective Association, Inc.” edited by ThomasTobin & Kent H. Stirling, which discusses the necessary withdrawal timesfor performance animals.

The DSI formulations disclosed herein may dissolve rapidly when incontact with the oral cavity and/or the non-gastric mucosa. In someembodiments, the immediate release formulations contemplated herein willdissolve when in contact with the oral cavity and/or the non-gastricmucosa in about 90 seconds or less. In some embodiments, the DSIformulation will dissolve in about 75 seconds or less, such as in about60 seconds or less about 45 seconds or less, about 30 seconds or less,or about 5 seconds or less. In some embodiments, the DSI formulationdissolves in less than about 3 seconds.

A further benefit of the DSI dosing of an animal is that the personadministering may be able to more quickly titrate an appropriate dosagefor the level and severity of the condition of the animal. Using typicalroutes of administration, due to metabolic disposition and the overallhealth of the animal, it may take a practitioner a period of severaldays to achieve an appropriate dose to treat and control a condition.One advantage of a DSI formulation is that the practitioner may reliablyassume therapeutic effects within a short period of time, and adjust thelevel of administration of the drug, as needed.

In at least some embodiments, DSI formulations permit a shorterwithdrawal time from treatment than with some conventional oral dosingregimens. By way of example only, typically, an equine patient will needto be withdrawn from many medications for periods ranging from 24-72hours prior to performance racing. This results in interruption of thetherapy, and can lead to a worsening of the existing disease, or at theleast, a slower recovery than if the withdrawal had not occurred. Inmany cases using DSI therapy, however, the equine patient may only needto discontinue the therapy for a period as short as 0-12 hours or not atall, depending upon the particular therapeutic agent being utilized inthe methods of the present disclosure.

In at least one exemplary embodiment, the methods herein areadministered to the circulatory system of the animal via a DSIformulation administered and absorbed in the oral cavity and/or thenon-gastric mucosa, adapted for humans, equines, bovines, canines,felines, ovines, and porcines, resulting in rapid absorption of theactive ingredient and faster clearance. Due to both administration andabsorption to the oral cavity and/or the non-gastric mucosa, theresultant effect is DSI.

Therapeutic agents which can be utilized in DSI formulations andadministered via the described methods include, but are not limited to,antibiotic, antibacterial, antifungal, antiviral, anti-inflammatory,anesthetic, analgesic, anti-allergic, corticosteroid, and mixturesthereof at any proportion. The concentration of said agents may beadapted to exert a therapeutic effect on a disease when applied to anafflicted animal, or human, by a practitioner skilled in the art.

A non-limiting list of exemplary therapeutic agents include abacavir,acebutolol, acepromazine, acrivastine, alatrofloxacin, albuterol,albendazole, alprazolam, alprenolol, amantadine, amiloride,aminoglutethimide, amiodarone, amitriptyline, amlodipine, amodiaquine,amoxapine, amphetamine, amphotericin, amprenavir, amrinone, amsacrine,astemizole, atenolol, atropine, azathioprine, azelastine, azithromycin,baclofen, benethamine, benidipine, benzhexol, benznidazole, benztropine,biperiden, bisacodyl, bisanthrene, brolliazepam, bromocriptine,bromperidol, brompheniramine, brotizolam, bupropion, butenafine,butoconazole, cambendazole, camptothecin, carbinoxamine, cephadrine,cephalexin, cetrizine, cinnarizine, chlorambucil, chlorpheniramine,chlorproguanil, chlordiazepoxide, chlorpromazine, chlorprothixene,chloroquine, cimetidine, ciprofloxacin, cisapride, citalopram,clarithromycin, clemastine, clemizole, clenbuterol, clofazimine,clomiphene, clonazepam, clopidogrel, clozapine, clotiazepam,clotrimazole, codeine, cyclizine, cyproheptadine, dacarbazine,darodipine, decoquinate, delavirdine, demeclocycline, detomidine,dexamphetamine, dexchlorpheniramine, dexfenfluramine, diamorphine,diazepam, diethylpropion, dihydrocodeine, dihydroergotamine, diltiazem,dimenhydrinate, diphenhydramine, diphenoxylate, diphenylimidazole,diphenylpyraline, dipyridamole, dirithromycin, disopyramide, dolasetron,domperidone, donepezil, doxazosin, doxycycline, droperidol, econazole,efavirenz, ellipticine, enalapril, enoxacin, enrofloxacin, eperisone,ephedrine, ergotamine, erythromycin, ethambutol, ethionamide,ethopropazine, etoperidone, famotidine, felodipine, fenbendazole,fenfluramine, fenoldopam, fentanyl, fexofenadine, flecainide,flucytosine, flunarizine, flunitrazepam, flunixin, fluopromazine,fluoxetine, fluphenthixol, fluphenthixol decanoate, fluphenazine,fluphenazine decanoate, flurazepam, flurithromycin, frovatriptan,gabapentin, granisetron, grepafloxacin, guanabenz, halofantrine,haloperidol, hyoscyamine, imipenem, imiprazole, indinavir, irinotecan,isoxazole, isoxsuprine HCl, isradipine, itraconazole, ketoconazole,ketotifen, labetalol, lamivudine, lanosprazole, leflunomide,levofloxacin, lisinopril, lomefloxacin, loperamide, loratadine,lorazepam, lormetazepam, lysuride, mepacrine, maprotiline, mazindol,mebendazole, meclizine, medazepam, mefloquine, melonicam, meptazinol,mercaptopurine, mesalamine, mesoridazine, metformin, methadone,methaqualone, methylphenidate, methylphenobarbital, methysergide,metoclopramide, metoprolol, metronidazole, mianserin, miconazole,midazolam, miglitol, minoxidil, misoprostol, mitomycins, mitoxantrone,molindone, montelukast, morphine, moxifloxacin, nadolol, nalbuphine,naratriptan, natamycin, nefazodone, nelfinavir, nevirapine, nicardipine,nicotine, nifedipine, nimodipine, nimorazole, nisoldipine, nitrazepam,nitrofurazone, nizatidine, norfloxacin, nortriptyline, nystatin,ofloxacin, olanzapine, omeprazole, ondansetron, omidazole, oxamniquine,oxantel, oxatomide, oxazepam, oxfendazole, oxiconazole, oxprenolol,oxybutynin, oxyphencyclimine, paroxetine, pentazocine, pentoxifylline,perchlorperazine, perfloxacin, pergolide, perphenazine, phenbenzamine,pheniramine, phenoxybenzamine, phentermine, physostigmine, pimozide,pindolol, pizotifen, pramipexol, pranlukast, praziquantel, prazosin,procarbazine, prochlorperazine, proguanil, propranolol, pseudoephedrine,pyrantel, pyrimethamine, quetiapine, quinidine, quinine, raloxifene,ranitidine, remifentanil, repaglinide, reserpine, ricobendazole,rifabutin, rifampin, rifapentine, rimantadine, risperidone, ritonavir,rizatriptan, ropinirole, rosiglitazone, roxaditine, roxithromycin,salbutamol, saquinavir, selegiline, sertraline, sibutramine, sildenafil,sparfloxacin, spiramycins, stavudine, sulconazole, sulphasalazine,sulpiride, sumatriptan, tacrine, tamoxifen, tamsulosin, temazepam,terazosin, terbinafine, terbutaline, terconazole, terfenadine,tetramisole, thiabendazole, thioguanine, thioridazine, tiagabine,ticlopidine, timolol, tinidazole, tioconazole, tirofiban, tizanidine,tolterodine, topotecan, toremifene, tramadol, trazodone, triamterene,triazolam, trifluoperazine, trimethoprim, trimipramine, tromethamine,tropicamide, trovafloxacin, vancomycin, venlafaxine, vigabatrin,vinblastine, vincristine, vinorelbine, vitamin KS, vitamin K6, vitaminK7, zafirlukast, zolmitriptan, zolpidem, zopiclone, acetazolamide,acetohexamide, acepromazine, acrivastine, alatrofloxacin, albuterol,alclofenac, aloxiprin, alprostadil, amodiaquine, amphotericin,amylobarbital, aspirin, atorvastatin, atovaquone, baclofen, barbital,benazepril, bezafibrate, bromfenac, bumetanide, butobarbital,candesartan, capsaicin, captopril, cefazolin, celecoxib, cephadrine,cephalexin, cerivastatin, cetrizine, chlorambucil, chlorothiazide,chlorpropamide, chlorthalidone, cinoxacin, ciprofloxacin, clinofibrate,cloxacillin, cromoglicate, cromolyn, dantrolene, dichlorophen,diclofenac, dicloxacillin, dicumarol, diflunisal, dimenhydrinate,divalproex, docusate, dronabinol, enoximone, enalapril, enoxacin,enrofloxacin, epalrestat, eposartan, essential fatty acids,estramustine, ethacrynic acid, ethotoin, etodolac, etoposide, fenbufen,fenoprofen, fexofenadine, fluconazole, flurbiprofen, fluvastatin,fosinopril, fosphenytoin, fumagillin, furosemide, gabapentin,gemfibrozil, gliclazide, glipizide, glybenclamide, glyburide,glimepiride, grepafloxacin, ibufenac, ibuprofen, imipenem, indomethacin,irbesartan, isotretinoin, ketoprofen, ketorolac, lamotrigine,levofloxacin, levothyroxine, lisinopril, lomefloxacin, losartan,lovastatin, meclofenamic acid, mefenamic acid, mesalamine, methotrexate,metolazone, montelukast, nalidixic acid, naproxen, natamycin,nimesulide, nitrofurantoin, non-essential fatty acids, norfloxacin,nystatin, ofloxacin, oxacillin, oxaprozin, oxyphenbutazone, penicillins,pentobarbital, perfloxacin, phenobarbital, phenytoin, pioglitazone,piroxicam, pramipexol, pranlukast, pravastatin, probenecid, probucol,propofol, propylthiouracil, quinapril, rabeprazole, repaglinide,rifampin, rifapentine, sparfloxacin, sulfabenzamide, sulfacetamide,sulfadiazine, sulfadoxine, sulfamerazine, sulfamethoxazole,sulfafurazole, sulfapyridine, sulfasalazine, sulindac, sulphasalazine,sulthiame, telmisartan, teniposide, terbutaline, tetrahydrocannabinol,tirofiban, tolazamide, tolbutamide, tolcapone, tolmetin, tretinoin,troglitazone, trovafloxacin, undecenoic acid, ursodeoxycholic acid,valproic acid, valsartan, vancomycin, verteporfin, vigabatrin, vitaminK-S(II), zafirlukast, and pharmaceutically acceptable oil-solublederivatives and salts thereof. For example, such salts include but arenot limited to clenbuterol HCl, flunixin meglumine, acepromazinemaleate, detomidine HCl.

Further are included altrenogest, amprolium, bacitracin zinc plusnicarbazin, butorphanol tartrate, cefevecin sodium, ceftiofur,cephapirin sodium, chlortetracycline, deracoxib, deslorelin acetate,dexmedetomidine hydrochloride, firocoxib, florfenicol, gentamicinsulfate and betamethasone valerate, gonadotropin releasingfactor-diphtheria toxoid conjugate, griseofulvin, hyaluronate sodium,imidacloprid, Ian phosphate, lasalocid, masitinib mesylate, melengestroJacetate and zilpaterol hydrochloride, milbemycin oxime, monensin usp,orbifloxacin, oxytetracycline, pirlimycin hydrochloride, polysulfatedglycosaminoglycan, progesterone, protamine zinc, ractopaminehydrochloride, ractopamine hydrochloride, robenacoxib, romycin,selamectin, semduramicin sodium biomass plus virginiamycin, sevoflurane,sevoflurane, spinosad, sulfachlorpyridazine sodium, tiamulin, toceranib,trilostane, tulathromycin, tylosin phosphate, tylosin tartrate, and anypharmaceutically acceptable substantially oil-soluble derivatives andsalts thereof.

Suitable anti-infective agents include, but are not limited toantibacterial, antifungal, antiviral, and anti-parasitic agents.

Specific macrolide antibiotics useful in various embodiments include butare not limited to erythromycin; sulfonamide (in its base form), such assulfanilamide, sulfadiazine and sulfacetamide; mupirocin; tetracyclines,such as tetracycline and doxycycline; synthetic and semi-synthesicpenicillins and beta-lactams; cloramphenicol; imidazoles; dicarboxylicacids, such as azelaic acid; salicylates; peptide antibiotics; andcyclic peptides, such as cyclosporine, tacrolimus, pimecrolimus andsirolimus (rapamycin). These antibiotics may be used in the treatment ofvarious antibacterial, antifungal, antiviral and parasitic infections inhumans, equines, bovines, ovines, canines, felines and porcines. Anotherembodiment according to the present disclosure utilizes ananti-inflammatory or anti-allergic as a therapeutic agent.Anti-inflammatory agents include but are not limited to corticosteroids,non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines,immunosuppressant agents, immunomodulators; and any combination thereofat a therapeutically effective concentration.

Another class of anti-inflammatory agents, which may be useful invarious embodiments of the present disclosure, includes the nonsteroidalanti-inflammatory agents (NSAIDs). The variety of compounds encompassedby this group is well-known to those skilled in the art. Somenon-steroidal anti-inflammatory agents useful in the compositionsdescribed herein include, but are not limited to: oxicams, such aspiroxicam, isoxicam, tenoxicam, sudoxicam; salicylates, such assalicylic acid, ethyl salicylate, methyl salycilate, aspirin, disalcid,benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal;acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin,sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin,acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, andketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic,niflumic, and tolfenamic acids; propionic acid derivatives, such asibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen,fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen,miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; andpyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone,azapropazone, and trimethazone.

Other therapeutic agents include diphenhydramine, doxepin, phrilaminemaleate, chlorpheniramine and tripelennamine, phenothiazines,promethazine hydrochloride and dimethindene maleate. These activeagents, as well as additional antihistamines can also be incorporatedinto a DSI formulation and utilized in the methods described herein totreat various respiratory and allergic conditions in animals.

In at least one embodiment, the therapeutic compositions describedherein comprise an anti-inflammatory or antiallergic agent, wherein saidagent reduces the occurrence of pro-inflammatory cytokines or inhibitsthe effect of pro-inflammatory cytokines. In one embodiment, thecompositions and methods described herein include mixtures ofanti-inflammatory agents, as well as the dermatologically acceptablesalts, esters, amides, prodrugs and derivatives of these agents. Suchagents may be utilized to treat numerous conditions where inflammationis present, either as a result of disease or injury, and include, butare not limited to muscle strains, arthritic conditions, jointdysplasia, infections etc.

Administration of a DSI formulation (e.g., immediate or rapid releaseformulation) according to various embodiments, e.g. comprising a safeand effective dose of an NSAID, can be useful in the prevention and/oralleviation of the symptoms of rheumatoid arthritis, osteoarthritis andpain. NSAIDs, incorporated in a fast acting formulation and administeredaccording to the methods of the present disclosure can be also used inthe treatment of dermatological disorders, such as acne, rosacea, hairgrowth disorders, actinic keratosis and certain skin cancer conditions.

In one embodiment, the therapeutic methods disclosed herein compriseadministering a DSI formulation (e.g., immediate or rapid releaseformulation) comprising an anti-inflammatory or antiallergic agent,wherein said agent reduces the occurrence of pro-inflammatory cytokinesor inhibits the effect of pro-inflammatory cytokines. Mixtures of suchanti-inflammatory agents may also be employed, as well as thedermatologically acceptable salts, esters, am ides, prodrugs andderivatives of these agents.

In one embodiment, the therapeutic methods disclosed herein compriseadministering a DSI formulation (e.g., immediate or rapid releaseformulation) comprising a safe and effective dose of an NSAID, for theprevention and/or alleviation of the symptoms of rheumatoid arthritis,osteoarthritis and/or pain.

In one embodiment, the therapeutic methods disclosed herein compriseadministering a DSI formulation (e.g., immediate or rapid releaseformulation) for the use in treating coat disorders comprisingadministering immunosuppressant agents, immunoregulating agents andimmunomodulators are chemically or biologically-derived agents thatmodify the immune response or the functioning of the immune system (asby the stimulation of antibody formation or the inhibition of whiteblood cell activity).

Immunosuppressant agents and immunomodulators include, among otheroptions, cyclic peptides, such as cyclosporine, tacrolimus, tresperimus,pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus, laquinimodand imiquimod. Such compounds, delivered sublingually in a immediaterelease formulation, are especially advantageous in coat disorders,where the large coat areas are to be treated.

In one embodiment, the therapeutic methods disclosed herein compriseadministering a DSI formulation (e.g., immediate or rapid releaseformulation) comprising a safe and effective amount of a topicalanesthetic. Examples of suitable anesthetic drugs include benzocaine,lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine,mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine,ketamine, pramoxine, phenol, and pharmaceutically acceptable saltsthereof. In one embodiment of the therapeutic methods, mixtures of suchanesthetic agents are administered and are synergistically beneficial.

In one embodiment, the therapeutic methods disclosed herein compriseadministering a DSI formulation (e.g., immediate or rapid releaseformulation) comprising anti-cancer agents to treat animal malignanttumors.

Advantageously, in at least some embodiments, DSI compositions accordingto the disclosure may ensure complete and accurate dosing with lessstress for both the animal and the animal handler. Further, the methodsof the disclosure may allow for higher concentrations of activeingredients, thereby minimizing the need for multiple dosing.

In one embodiment, DSI provides for methods of treating and controllingconditions in an animal, comprising administering to said animal aneffective amount of a therapeutic agent in a DSI composition (e.g.,immediate or rapid release formulation) which comprises: about 0.5% toabout 50% wt/wt of active ingredient together with excipients to a totalof about 100% wt/wt.

In further embodiments, DSI provides for methods of treating andcontrolling conditions in an animal, comprising administering to saidanimal an effective amount of a therapeutic agent in a DSI composition(e.g., immediate or rapid release formulation) which comprises, forexample, about 1.0% to about 10% wt/wt of active ingredient togetherwith excipients to a total of about 100% wt/wt.

In further embodiments, DSI provides for methods of treating andcontrolling conditions in an animal, comprising administering to saidanimal an effective amount of a therapeutic agent in a DSI composition(e.g., immediate or rapid release formulation) which comprises, forexample, about 5% by weight of active ingredient together withexcipients to a total of about 100% wt/wt.

Effective amounts may vary according to various factors, such as, butnot limited to, the general health of the animal, the degree or severityof the particular disease under treatment, the age of the animal, theorgans infected or infested, and the like. In at least one embodiment ofthe therapeutic methods disclosed herein, the amount of the DSIcompositions is sufficient to provide therapeutic levels of the activeingredient as quickly as possible.

In an exemplary embodiment where the active ingredient is clenbuterol,the amount of a non-limiting and exemplary DSI composition administeredis that sufficient to provide about 0.2 meg/kg to about 3.0 meg/kg ofactive ingredient per body weight of the animal and about 0.4 meg/kg toabout 1.5 meg/kg, most preferably about 0.8 meg/kg of active ingredientper body weight of the animal. In one embodiment the compositioncomprises about 0.36 mg clenbuterol/tablet. For example, in oneembodiment, the composition comprises 0.363 mg of clenbuterol per tabletto treat recurrent airway inflammation (RAI) in horses by significantlyincreasing mucociliary transport in horses with RAI.

In further embodiments, the methods of treatment disclosed hereincomprise administering DSI compositions of clenbuterol for the treatmentof a central nervous system disorder. For example, in one embodiment,the methods of treatment comprise administering DSI compositions ofclenbuterol for treating Parkinson's Disease to a patient in needthereof.

In a further exemplary embodiment where the active ingredient isomeprazole, the amount of said DSI composition administered is thatsufficient to provide about 0.5 mg/kg to about 8.0 mg/kg of activeingredient per body weight of the animal and about 1.0 mg/kg to about6.0 mg/kg, about 4.0 mg/kg of active ingredient per body weight of theanimal, with an approximate amount of about 350-550 mg omeprazole/dose.Imiprazole, or histamine type-2 receptor antagonists (such as cimetidineor ranitidine), or other proton pump inhibitors such as pantoprazole areused to suppress gastric acidity and to heal and prevent gastric ulcers.

In a further exemplary embodiment, where the active ingredient isomeprazole, the amount of said DSI composition administered is thatsufficient to provide omeprazole at a pH of greater than about 6. Inother exemplary embodiments, omeprazole is administered at a pH of about10.

When the active ingredient is tramadol, the amount of the DSIcomposition administered is sufficient to provide about 0.5 mg/kg toabout 8.0 mg/kg of active ingredient per body weight of the animal andabout 0.75 mg/kg to about 6.0 mg/kg, about 1 to about 4 mg/kg of activeingredient per body weight of the animal. In one embodiment the amountof tramadol DSI composition is about 4.5 to about 18 mg tramadol/tablet.In at least one embodiment, the therapeutic methods compriseadministering tramadol for the treatment of pain. In at least onefurther embodiment, the therapeutic methods comprise administeringcodeine for the treatment of pain. In yet a further embodiment, thetherapeutic methods comprise administering codeine for the treatment ofcoughing as an analgesic. In yet a further embodiment, the therapeuticmethods comprise administering codeine for the treatment of coughing. Inyet a further embodiment, the therapeutic methods comprise administeringcodeine for the induction of sedation before surgery and/or as asupplement to anesthesia.

When the active ingredient is guanabenz, for example, the amount of theDSI composition administered may be chosen such that it is sufficient toprovide about 0.33 mg/kg to, about 2.0 mg/kg of active ingredient perbody weight of the animal and about 0.44 mg/kg to about 1.0 mg/kg, about0.66 mg/kg of active ingredient per body weight of the animal, with anapproximate amount of about 300 mg guanabenz/tablet. In one exemplaryembodiment, the therapeutic methods comprise administering guanabenz toan animal to reduce the blood pressure in the animal's pulmonarycirculatory tract and thereby reduce the incidence and/or severity ofexercise-induced pulmonary hemorrhage. In a further exemplaryembodiment, the therapeutic methods comprise administering guanabenz toan animal as a sedative.

When the active ingredient is furosemide, for example, the amount of theDSI composition administered may be chosen such that it is sufficient toprovide about 0.10 mg/kg to about 2.0 mg/kg of active ingredient perbody weight of the animal and about 0.25 mg/kg to about 1.5 mg/kg. Inone exemplary embodiment, the therapeutic methods comprise administeringfurosemide to an animal about 0.5 to about 1.0 mg/kg of activeingredient per body weight of the animal, with an approximate amount ofabout 50 to about 450 mg furosemide/tablet. In a further exemplaryembodiment, the therapeutic methods comprise administering furosemide toan animal as a diuretic. In one embodiment the therapeutic methodscomprise administering furosemide to an animal to treat pulmonary edema.In yet a further embodiment, the therapeutic methods compriseadministering furosemide to an animal to treat congestive heart failurein combination with other drugs. In yet a further embodiment, thetherapeutic methods comprise administering furosemide to an animal totreat allergic reactions. In yet further embodiments, the therapeuticmethods comprise administering furosemide to an animal to reduce theincidence of exercise-induced pulmonary hemorrhage (EIPH) (a.k.a.“bleeding”) by animals during races.

When the active ingredient is ivermectin, for example, the amount of theDSI composition administered may be chosen such that it is sufficient toprovide about 0.05 mg/kg to about 0.4 mg/kg of active ingredient perbody weight of the animal and about 0.1 mg/kg to about 0.3 mg/kg, about0.2 mg/kg of active ingredient per body weight of the animal, with anapproximate amount of about 90 mg ivermectin/tablet. In one exemplaryembodiment, the therapeutic methods comprise administering ivermectin toan animal to treat numerous parasites in animals including humans,horses, cows, dogs, pigs and sheep such as large strongyles, smallstrongyles, pinworms, ascarids, hairworms, large-mouth stomach worms,bats, lungworms, intestinal threadworms, to name a few. In an exemplaryembodiment, the therapeutic methods comprise administering ivermectin toan animal to control summer sores caused by bots. In yet a furtherexemplary embodiment, the therapeutic methods comprise administeringivermectin to an animal to treat dermatitis caused by neck threadworms.

When the active ingredient is carprofen, for example, the amount of OSIcomposition administered may be chosen such that it is sufficient toprovide about 0.2 mg/kg to about 4.0 mg/kg of active ingredient per bodyweight of the animal and about 0.45 mg/kg to about 2.0 mg/kg, about 1.0mg/kg of active ingredient per body weight of the animal, with anapproximate amount of about 400 mg carprofen/tablet. In one embodiment,for example, the therapeutic method comprises administering carprofen toan animal to treat arthritis in animals. As used herein “arthritis”includes both short term, for joint pain or post-operative inflammation,or for day-to-day relief from the pain and inflammation associated withosteoarthritis, hip dysplasia, and other forms of joint deterioration.Its use may reduce inflammation by inhibiting the production of COX-2and other sources of inflammatory prostaglandins.

When the active ingredient is flunixin meglumine, for example, theamount of the OSI composition administered may be chosen such that it issufficient to provide about 0.25 mg/kg to about 4.4 mg/kg of activeingredient per body weight of the animal and about 0.55 mg/kg to about2.2 mg/kg, about 1.1 mg/kg of active ingredient per body weight of theanimal, with an approximate amount of about 500 mg flunixinmeglemune/tablet. In one exemplary embodiment, the therapeutic methodcomprises administering flunixin meglumine to an animal to treat pain.In yet another embodiment, the therapeutic method comprisesadministering flunixin meglumine to an animal for treating colic. In afurther exemplary embodiment, the therapeutic method comprisesadministering flunixin meglumine to an animal for treatingseptic/endotoxic shock due to any gastrointestinal (GI) insult eitherpost-surgical or medical such as in cases of peritonitis or diarrhea. Inyet a further exemplary embodiment, the therapeutic method comprisesadministering flunixin meglumine to an animal for treating used as ananti-inflammatory to treat painful conditions of the eye includingcorneal ulcers, uveitis, conjunctivitis and before and after eyesurgery. In yet a further exemplary embodiment, the therapeutic methodcomprises administering flunixin meglumine to an animal for treatingfevers due to viral or bacterial infections.

Other active ingredients for use in the methods disclosed hereininclude, but are not limited to, those such as albuterol, cromolyn,dantrolene, domperidone, isoxsuprine HCl, ketoprofen, misoprostol,pergolide, phenylbutazone, phenytoin and reserpine.

As described herein, homeothermic animals suitable for treatment in thedisclosed methods include, for example, humans, equine, bovine, ovine,swine, caprine, canine, feline or the like animals, or any for whommetabolic disposition of an active is problematic, or for which initialdose titration may pose risks, or which is otherwise undesirable.

The above disclosed doses and dosage ranges are not intended to belimiting. A practitioner skilled in the art may likewise administersuitable DSI compositions (e.g., immediate or rapid release formulation)in single or divided doses, according to the desired therapeutic effect.Thus, in certain clinical situations it may be desirable to administercompositions to give initial high levels of the active ingredient,followed by lower dose maintenance doses.

In the compositions and methods described herein, where a particularcompound is recited applicants contemplate isolated enantiomers andmixtures thereof in any proportions. For example, where the term“clenbuterol” is used, applicants contemplate either or both of the R.and/or S-enantiomers.

It is to be understood that the foregoing description is exemplary andexplanatory only, and not to be interpreted as restrictive of thedisclosure. Various modifications of this disclosure, in addition tothose shown and described herein, will become apparent to those skilledin the art from the following examples and the foregoing description.Such modifications are also intended to fall within the scope of thepresent disclosure. Other embodiments will be apparent to those skilledin the art from consideration of the disclosure and practice of thevarious exemplary embodiments disclosed herein.

It is also to be understood that, as used herein the terms “the,” “a,”or “an,” mean “at least one,” and should not be limited to “only one”unless explicitly indicated to the contrary. Thus, for example, the useof “a therapeutic agent” is intended to mean at least one therapeuticagent.

Unless otherwise indicated, all numbers used in the specification andclaims are to be understood as being modified in all instances by theterm “about,” whether or not so stated. It should also be understoodthat the precise numerical values used in the specification and claimsform additional embodiments of the disclosure, and are intended toinclude any ranges which can be narrowed to any two end points disclosedwithin the exemplary ranges and values provided. Efforts have been madeto ensure the accuracy of the numerical values disclosed herein. Anymeasured numerical value, however, can inherently contain certain errorsresulting from the standard deviation found in its respective measuringtechnique.

What is claimed is:
 1. A method of treating recurrent airwayinflammation in an animal in need thereof, the method comprising:determining a dose of clenbuterol required; and administering orally toa pre-gastric mucosal cell of the animal a Direct Systemic Introduction(DSI) composition comprising clenbuterol, wherein the DSI composition inthe animal's oral cavity is dissolved in less than about 75 seconds, andwherein the required dose of clenbuterol is determined by greater than50% of the administered clenbuterol being detected in the animal'scirculatory system via the pre-gastric mucosal cells lining the animal'salimentary canal prior to the animal's secretory stomach.
 2. The methodaccording to claim 1, wherein the DSI composition is dissolved in lessthan about 30 seconds.
 3. The method according to claim 1, wherein theDSI composition is dissolved in less than about 5 seconds.
 4. The methodaccording to claim 1, wherein the clenbuterol is present in the DSIcomposition in an amount ranging from about 0.5% to about 50% by weightof the overall composition.
 5. The method according to claim 1, whereinthe clenbuterol is in the form of a free base; a water soluble salt; oran isolated single enantiomer or mixture thereof.
 6. The methodaccording to claim 1, wherein the animal is human.
 7. The methodaccording to claim 1, wherein the animal is an equine.
 8. The methodaccording to claim 1, wherein the DSI composition further comprises atleast one excipient.
 9. The method according to claim 1, wherein the DSIcomposition provides an immediate release of clenbuterol.
 10. The methodaccording to claim 1, wherein the DSI composition is in the form of atablet comprising about 0.36 mg of clenbuterol.
 11. The method accordingto claim 1, wherein the DSI composition is formulated to provide about0.2 mcg/kg to about 3.0 mcg/kg of clenbuterol per body weight of theanimal.
 12. A method of treating a central nervous system disorder in ananimal in need thereof, the method comprising: determining a dose ofclenbuterol required; and administering orally to a pre-gastric mucosalcell of the animal a Direct Systemic Introduction (DSI) compositioncomprising clenbuterol, wherein the DSI composition in the animal's oralcavity is dissolved in less than about 75 seconds, and wherein therequired dose of clenbuterol is determined by greater than 50% of theadministered clenbuterol being detected in the animal's circulatorysystem via the pre-gastric mucosal cells lining the animal's alimentarycanal prior to the animal's secretory stomach.
 13. The method accordingto claim 12, wherein the central nervous system disorder is Parkinson'sDisease.
 14. The method according to claim 12, wherein the DSIcomposition is dissolved in less than about 30 seconds.
 15. The methodaccording to claim 12, wherein the DSI composition is dissolved in lessthan about 5 seconds.
 16. The method according to claim 12, wherein theclenbuterol is present in the DSI composition in an amount ranging fromabout 0.5% to about 50% by weight of the overall composition.
 17. Themethod according to claim 12, wherein the clenbuterol is in the form ofa free base; a water soluble salt; or an isolated single enantiomer ormixture thereof.
 18. The method according to claim 12, wherein theanimal is human.
 19. The method according to claim 12, wherein theanimal is an equine.
 20. The method according to claim 12, wherein theDSI composition further comprises at least one excipient.
 21. The methodaccording to claim 12, wherein the DSI composition provides an immediaterelease of clenbuterol.